WO2007039322A1 - Utilisation de composes a base de vitamine d3 pour traiter l'uveite - Google Patents

Utilisation de composes a base de vitamine d3 pour traiter l'uveite Download PDF

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WO2007039322A1
WO2007039322A1 PCT/EP2006/061415 EP2006061415W WO2007039322A1 WO 2007039322 A1 WO2007039322 A1 WO 2007039322A1 EP 2006061415 W EP2006061415 W EP 2006061415W WO 2007039322 A1 WO2007039322 A1 WO 2007039322A1
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compound
vitamin
formulation
kit
alkyl
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PCT/EP2006/061415
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Luciano Adorini
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Bioxell Spa
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to novel uses and methods, and compounds for use therein.
  • Uveitis a condition comprising inflammation of the eye including the iris, ciliary body, and choroid, actually comprises a large group of diverse diseases affecting not only the uvea but also the retina, optic nerve and vitreous.
  • uveitis anterior, intermediate, posterior and panuveitis (total). Inflammation may be induced by trauma or toxic or infectious agents, but in most cases the mechanisms seem to be autoimmune in nature. Symptoms may be acute, sub-acute, chronic (greater than 3 months duration) and recurrent. The etiology is unknown in the majority of cases of endogenous uveitis. Uveitis is a major cause of severe visual impairment. Although the number of patients blinded from uveitis is unknown, it has been estimated that uveitis accounts for 10-15% of all cases of total blindness in the USA.
  • posterior uveitis focal, multifocal or diffuse choroiditis, chorioretinitis, retinochoroiditis, uveoretinitis or neurouveitis.
  • the condition is usually painless but is characterised by the presence of floaters, vision impairment (sudden or gradual) such as blurring of vision, etc., and vision loss.
  • Posterior uveitis may have several etiologies, and manifests itself in complex and sometimes misleading clinical conditions. There is growing evidence both in experimental models and clinically that endogenous posterior uveoretinitis is often characterised by an exaggerated immune response which causes tissue destruction.
  • treatment can be directed towards dampening the resulting inflammatory cascade and hopefully reducing tissue damage.
  • the mainstay of treatment is systemic corticosteroid and often this is given in combination with immunosuppressive agents, such as cyclosporin A or azathioprine.
  • immunosuppressive agents such as cyclosporin A or azathioprine.
  • High dose steroids are often required to control the disease and in addition to the disadvantages of the required longterm use and resistance in some patients, potentially serious side effects are often present.
  • weight gain particularly around the face, which can be cosmetically unacceptable.
  • Another important side effect of corticosteroids, particularly with reference to the eye is glaucoma resulting from increased intraocular pressure.
  • the present inventors have developed a new method of treating uveitis with a view to mitigating or alleviating the aforementioned disadvantages.
  • the method is based on the use of calcitriol and analogs thereof, collectively "vitamin D compounds”.
  • vitamin D cholesterol calcium and phosphorus homeostasis
  • the operation of the vitamin D endocrine system depends on the following: first, on the presence of cytochrome P450 enzymes in the liver (Bergman, T. and Postlind, H. (1991) Biochem. J. 276:427-432; Ohyama, Y and Okuda, K. (1991) J. Biol. Chem. 266:8690-8695) and kidney (Henry, H.L. and Norman, A.W. (1974) J. Biol. Chem. 249:7529-7535; Gray, R.W. and Ghazarian, J. G. (1989) Biochem. J.
  • Vitamin D 3 and its hormonally active forms are well-known regulators of calcium and phosphorus homeostasis. These compounds are known to stimulate, at least one of, intestinal absorption of calcium and phosphate, mobilization of bone mineral, and retention of calcium in the kidneys. Furthermore, the discovery of the presence of specific vitamin D receptors in more than 30 tissues has led to the identification of vitamin D 3 as a pluripotent regulator outside its classical role in calcium/bone homeostasis.
  • a paracrine role for 1 -alpha, 25(OH) 2 D 3 has been suggested by the combined presence of enzymes capable of oxidizing vitamin D 3 into its active forms, e.g., 25-OHD-1-alpha-hydroxylase, and specific receptors in several tissues such as bone, keratinocytes, placenta, and immune cells.
  • enzymes capable of oxidizing vitamin D 3 into its active forms e.g., 25-OHD-1-alpha-hydroxylase
  • specific receptors e.g., 25-OHD-1-alpha-hydroxylase
  • specific receptors e.g., 25-OHD-1-alpha-hydroxylase
  • specific receptors e.g., 25-OHD-1-alpha-hydroxylase
  • vitamin D 3 hormone and active metabolites have been found to be capable of regulating cell proliferation and differentiation of both normal and malignant cells (Reichel, H. et al. (1989) Ann. Rev. Med. 40: 71-78).
  • vitamin D and its structural analogues have been limited by the undesired side effects elicited by these compounds after administration to a subject for known indications/applications of vitamin D compounds.
  • vitamin D The activated form of vitamin D, vitamin D 3 , and some of its analogues have been described as potent regulators of cell growth and differentiation. It has previously been found that vitamin D 3 as well as an analogue (analogue V), inhibited BPH cell proliferation and counteracted the mitogenic activity of potent growth factors for BPH cells, such as keratinocyte growth factor (KGF) and insulin-like growth factor (IGF1). Moreover, the analogue induced bcl-2 protein expression, intracellular calcium mobilization, and apoptosis in both unstimulated and KGF-stimulated BPH cells.
  • KGF keratinocyte growth factor
  • IGF1 insulin-like growth factor
  • Topical administration of calcitriol has been said to inhibit Langerhans cell migration and corneal neovascularisation in ocular surface inflammation (Suzuki et al (2000) Curr. Eye Res. 20(2) 127-130) and calcitriol has been said to inhibit the P aeruginosa-induced expression of IL- 1b, IL-6 and IL-8 in human corneal epithelial cells (Xue et al (2002) Immunol. Cell Biol. 80(4) 340-5).
  • the cornea is a distinct part of the eye, separate from those internal and posterior parts of the eye which are treated according to the methods of the present invention.
  • the cornea is accessible by topical treatment (direct administration to the cornea) which would not be the route of choice in the context of the present invention (for which systemic administration would be especially suitable).
  • vitamin D compounds such as calcitriol and an analogue of calcitriol (“Compound A") can prevent experimental autoimmune uveoretinitis (EAU), an autoimmune disease mediated by Th 1 -type uveitogenic CD4+ T cells that serves as a model for human posterior uveitis.
  • EAU experimental autoimmune uveoretinitis
  • Th 1 -type uveitogenic CD4+ T cells that serves as a model for human posterior uveitis.
  • the invention provides the use of a vitamin D compound in the prevention or treatment of uveitis. Also provided is a method of treating a patient with uveitis by administering an effective amount of a vitamin D compound. Further provided is the use of a vitamin D compound in the manufacture of a medicament for the prevention or treatment of uveitis. Further provided is a vitamin D compound for use in the prevention or treatment of uveitis. Additionally provided is a pharmaceutical combination comprising a vitamin D compound and a further agent for the treatment or prevention of uveitis. Also provided is a kit comprising a vitamin D compound together with instructions directing administration of said compound to a patient in need of treatment or prevention of uveitis thereby to treat or prevent uveitis in said patient.
  • the invention provides a method of prevention or treatment of uveitis using a vitamin D compound.
  • the invention provides a method for preventing or treating uveitis in a subject, comprising administering to a subject in need thereof an effective amount of a vitamin D compound, such that the uveitis is prevented or treated in the subject.
  • the invention provides a method as described above, further comprising identifying a subject in need of prevention or treatment for uveitis. In another embodiment, the invention provides a method as described above, further comprising the step of obtaining the vitamin D compound. According to the methods described herein, the subject is typically a mammal, particularly a human. In another embodiment, the invention provides a method described herein wherein the vitamin D compound is formulated in a pharmaceutical composition together with a pharmaceutically acceptable diluent or carrier. In another aspect, the invention provides a pharmaceutical formulation comprising a vitamin D compound and a pharmaceutically acceptable carrier for use in the prevention or treatment of uveitis.
  • the invention provides a pharmaceutical formulation comprising a vitamin D compound and a pharmaceutically acceptable carrier packaged with instructions for use in the prevention or treatment of uveitis.
  • the invention provides a vitamin D compound for preventing or treating uveitis.
  • the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is administered separately, sequentially or simultaneously in separate or combined pharmaceutical formulations with a second medicament for the prevention or treatment of uveitis.
  • the vitamin D compound is not a compound represented by formula (I):
  • a 1 is single or double bond;
  • a 2 is a single, double or triple bond;
  • R 1 and R 2 are each independently OC(O)C 1 -C 4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl;
  • R 3 , R 4 and R 5 are each independently hydrogen, CrC 4 alkyl, hydroxyalkyl, or haloalkyl, with the understanding that R 5 is absent when A 2 is a triple bond, or R 3 and R 4 taken together with C 20 form C 3 -C 6 cycloalkyl;
  • R 6 and R 7 are each independently alkyl or haloalkyl; and
  • R 8 is H, C(O)C 1 -C 4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; provided that when A 1 is
  • the vitamin D compound is a compound of formula (I), as follows:
  • a 1 is single or double bond
  • a 2 is a single, double or triple bond
  • R 1 and R 2 are each independently OC(O)C 1 -C 4 alkyl (e.g.
  • R 1 and R 2 may each also independently represent OH;
  • R 3 , R 4 and R 5 are each independently hydrogen, CrC 4 alkyl, hydroxyalkyl, or haloalkyl, with the understanding that R 5 is absent when A 2 is a triple bond, or R 3 and R 4 taken together with C 20 form C 3 -C 6 cycloalkyl;
  • R 6 and R 7 are each independently alkyl (e.g.
  • R 8 is H, C(O)C 1 -C 4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • Particular compounds of formula (I) that may be mentioned for use in the context of the invention are those wherein A 1 is a single bond, R 3 is hydrogen, R 4 is methyl, and A 2 is a double or triple bond.
  • R 1 and R 2 are OH or OC(O)C 1 -C 4 alkyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 1 and R 2 are OAc.
  • the invention provides for use, method, formulation, compound or kit, wherein A 1 is single bond and A 2 is a single bond.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 3 and R 4 taken together with C 20 form C 3 -C 6 cycloalkyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 3 and R 4 taken together with C 20 form cyclopropyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 5 is hydrogen.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 6 and R 7 are each independently C 1-4 alkyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 6 and R 7 are each independently methyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 8 is H.
  • the invention provides for the use, method, formulation, compound or kit, wherein R 1 and R 2 are OH or OAc, R 3 and R 4 taken together with C 20 form cyclopropyl, and R 6 and R 7 are each methyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein said vitamin D compound is a compound of the formula (II):
  • X is H 2 or CH 2
  • Ri is hydrogen, hydroxy or fluorine
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or methyl provided that when R 2 or R 3 is methyl, R 3 or R 2 must be hydrogen
  • R 4 is methyl, ethyl or trifluoromethyl
  • R 5 is methyl, ethyl or trifluoromethyl
  • A is a single or double bond
  • B is a single, E-double, Z-double or triple bond.
  • the invention provides for the use, method, formulation, compound, or kit, wherein in the compound of formula (II) each of R 4 and R 5 is methyl or ethyl.
  • the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is 1,3-Di-O-acetyl-1 ,25-dihydroxy-20- cyclopropyl-cholecalciferol (hereinafter sometimes referred to as "Compound A”) having the formula:
  • the vitamin D compound is not 1,3-Di-O-acetyl-1 ,25-dihydroxy- 20-cyclopropyl-cholecalciferol.
  • the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is I ⁇ S-dihydroxy ⁇ O ⁇ i ⁇ -cyclopropyl- cholecalciferol having the formula:
  • the vitamin D compound is not 1,3-Di-O-acetyl-1 ,25-dihydroxy- 20-cyclopropyl-cholecalciferol.
  • the invention provides for the use, method, formulation, compound or kit, wherein the vitamin D compound is 1-alpha-fluoro-25-hydroxy-16,23E-diene- 26,27-bishomo-20-epi-cholecalciferol, having the formula:
  • the invention provides for the use, method, formulation, compound or kit wherein the compound is calcitriol.
  • the invention provides for the use, method, formulation, compound or kit, wherein said uveitis is autoimmune uveitis.
  • the invention provides for the use, method, formulation, compound or kit, wherein said uveitis is posterior uveitis and in particular is uveoretinitis.
  • Figure 1 shows the experimental procedure used to treat experimental autoimmune uveoretinitis (EAU) with Compound A.
  • FIG. 2 shows the EAU disease score (quantitated between 0 and 4) at day 21.
  • Figure 3 shows the reduced antigen-specific delayed type hypersensitivity (DTH) responses to IRBP in mice.
  • DTH delayed type hypersensitivity
  • Figure 4 shows the in vitro assay of primed lymph node cells (LN) used to indicated that calcitriol and Compound A both appeared to be potent on T cell polarization.
  • LN primed lymph node cells
  • FIG. 5 shows that Ag driven chemokine release, such as MIP-Ia, Rantes and TARC, is inhibited by Vitamin D compounds.
  • uveitis conditions comprising inflammation of the eye, in particular the uveal tract (iris, ciliary body, choroid) with or without additional inflammation of the retina, optic nerve and vitreous, including but not limited to anterior, intermediate, posterior uveitis and panuveitis and in acute, sub-acute, chronic or recurrent forms.
  • the methods of the invention are applicable, for example, to the treatment of posterior uveitis including but not limited to focal, multifocal or diffuse choroiditis, chorioretinitis, retinochoroiditis uveretinitis or neurouveitis.
  • posterior uveitis including but not limited to focal, multifocal or diffuse choroiditis, chorioretinitis, retinochoroiditis uveretinitis or neurouveitis.
  • Such types of uveitis may by caused by an autoimmune response or a disordered immune response (for example where inflammation continues after infecting bacteria have been removed).
  • Most typically the posterior uveitits is uveoretinitis.
  • the vitamin D compounds may be used in human or veterinary medicine.
  • the terms “subject” and “patient” are used interchangeably, and are intended to include mammals, for example, humans. It is preferred that the vitamin D compound be used in the treatment of human patients.
  • administration includes routes of introducing the vitamin D compound(s) to a subject to perform their intended function.
  • routes of administration include injection (subcutaneous, intravenous, parenterally, intraperitoneally), oral, inhalation, rectal, transdermal, or ocular delivery.
  • the pharmaceutical preparations are, of course, given by forms suitable for each administration route. For example, these preparations are administered in tablets or capsule form, by injection, infusion, inhalation, lotion, ointment, suppository, etc. Oral administration is preferred.
  • the injection can be bolus or can be continuous infusion.
  • the vitamin D compound can be coated with or disposed in a selected material to protect it from natural conditions which may detrimentally effect its ability to perform its intended function.
  • the vitamin D compound can be administered alone, or in conjunction with either another agent useful in the treatment of uveitis (for example corticosteroids), or with a pharmaceutically-acceptable carrier, or both.
  • the vitamin D compound can be administered prior to the administration of the other agent, simultaneously with the agent, or after the administration of the agent (via the same or different routes).
  • the vitamin D compound can also be administered in a pro-form which is converted into its active metabolite, or more active metabolite in vivo.
  • an effective amount includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, i.e. sufficient to treat uveitis.
  • An effective amount of vitamin D compound may vary according to factors such as the disease state, age and weight of the subject, and the ability of the vitamin D compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the vitamin D compound are outweighed by the therapeutically beneficial effects.
  • a therapeutically effective amount of vitamin D compound may range from about 0.001 to 30 ug/kg body weight, preferably about 0.01 to 25 ug/kg body weight, more preferably about 0.1 to 20 ug/kg body weight, and even more preferably about 1 to 10 ug/kg, 2 to 9 ug/kg, 3 to 8 ug/kg, 4 to 7 ug/kg, or 5 to 6 ug/kg body weight (for example, per day).
  • an effective dosage may range from about 0.001 to 30 ug/kg body weight, preferably about 0.01 to 25 ug/kg body weight, more preferably about 0.1 to 20 ug/kg body weight, and even more preferably about 1 to 10 ug/kg, 2 to 9 ug/kg, 3 to 8 ug/kg, 4 to 7 ug/kg, or 5 to 6 ug/kg body weight (for example, per day).
  • certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of
  • the dose administered will also depend on the particular vitamin D compound used.
  • the effective amount of each compound can be determined by titration methods known in the art.
  • treatment of a subject with a therapeutically effective amount of a vitamin D compound can include a single treatment or, preferably, can include a series of treatments.
  • a subject is treated with a vitamin D compound in the range of between about 0.1 to 20 ug/kg body weight, one time per day for a duration of six months or longer, for example for life, depending on management of the symptoms and the evolution of the condition.
  • alkyl refers to the radical of saturated aliphatic groups, including straight- chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • alkyl further includes alkyl groups, which can optionally further include (for example, in one embodiment alkyl groups do not include) oxygen, nitrogen, sulfur or phosphorus atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen, sulfur or phosphorus atoms.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., CrC 30 for straight chain, C 3 -C 30 for branched chain), preferably 26 or fewer, and more preferably 20 or fewer, especially 6 or fewer (for example 4 for fewer).
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3, 4, 5, 6 or 7 carbons in the ring structure.
  • alkyl as used throughout the specification and claims is intended to include both “unsubstituted alkyls” and “substituted alkyls,” the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • substituents can include, for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoro
  • alkylaryl moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (benzyl)).
  • aryl e.g., phenylmethyl (benzyl)
  • alkyl also includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively (i.e. alkenyl and alkynyl groups).
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six, and most preferably from one to four carbon atoms in its backbone structure, which may be straight or branched-chain.
  • lower alkyl groups include methyl, ethyl, propyl (n- propyl and i-propyl), butyl (tert-butyl, n-butyl and sec-butyl), pentyl, hexyl, heptyl, octyl and so forth.
  • the term "lower alkyl” includes a straight chain alkyl having 4 or fewer carbon atoms in its backbone, e.g., d-C 4 alkyl.
  • alkyl examples include CrC 6 alkyl or Ci-C 4 alkyl (such as methyl or ethyl).
  • hydroxyalkyl examples include C r C 6 hydroxyalkyl or C r C 4 hydroalkyl (such as hydroxy methyl).
  • alkoxyalkyl refers to alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone, e.g., oxygen, nitrogen or sulfur atoms.
  • aryl refers to the radical of aryl groups, including 5- and 6- membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, benzoxazole, benzothiazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl groups also include polycyclic fused aromatic groups such as naphthyl, quinolyl, indolyl, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as
  • aryl heterocycles "heteroaryls” or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, as for example, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydr ⁇ l, alkylthio, ar ⁇ lthio, thio
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogueous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively.
  • the invention contemplates cyano and propargyl groups.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • diastereomers refers to stereoisomers with two or more centers of dissymmetry and whose molecules are not mirror images of one another.
  • enantiomers refers to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • An equimolar mixture of two enantiomers is called a “racemic mixture” or a “racemate.”
  • halogen designates -F, -Cl, -Br or -I; the term “sulfhydryl” or “thiol” means -SH; the term “hydroxyl” means -OH.
  • haloalkyl is intended to include alkyl groups as defined above that are mono- , di- or polysubstituted by halogen, e.g., C r6 haloalkyl or C r4 haloalkyl such as fluoromethyl and trifluoromethyl.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus.
  • polycyclyl or “polycyclic radical” refer to the radical of two or more cyclic rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, sulfonato, sulfamoyl,
  • isomers or “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • an isolated vitamin D compound is at least 75% pure, especially at least 85% pure, in particular at least 95% pure and preferably at least 99% pure on a w/w basis, said purity being by reference to compounds with which the vitamin D compound is naturally associated or else chemically associated in the course of chemical synthesis.
  • the terms “isolated” or “substantially purified” also refer to preparations of a chiral compound which substantially lack one of the enantiomers; i.e., enantiomerically enriched or non-racemic preparations of a molecule.
  • isolated epimers or “isolated diastereomers” refer to preparations of chiral compounds which are substantially free of other stereochemical forms.
  • isolated or substantially purified vitamin D 3 compounds include synthetic or natural preparations of a vitamin D 3 enriched for the stereoisomers having a substituent attached to the chiral carbon at position 3 of the A-ring in an alpha-configuration, and thus substantially lacking other isomers having a beta-configuration. Unless otherwise specified, such terms refer to vitamin D 3 compositions in which the ratio of alpha to beta forms is greater than 1 :1 by weight.
  • an isolated preparation of an a epimer means a preparation having greater than 50% by weight of the alpha-epimer relative to the beta stereoisomer, more preferably at least 75% by weight, and even more preferably at least 85% by weight.
  • the enrichment can be much greater than 85%, providing "substantially epimer-enriched" preparations, i.e., preparations of a compound which have greater than 90% of the alpha-epimer relative to the beta stereoisomer, and even more preferably greater than 95%.
  • the term "substantially free of the beta stereoisomer" will be understood to have similar purity ranges.
  • vitamin D compound includes any compound being an analogue of vitamin D that is capable of treating or preventing uveitis.
  • compounds which are ligands for the Vitamin D receptor (VDR ligands) and which are capable of treating or preventing uveitis are considered to be within the scope of the invention.
  • Vitamin D compounds are preferably agonists of the vitamin D receptor.
  • vitamin D compounds are intended to include secosteroids. Examples of specific vitamin D compounds suitable for use in the methods of the present invention are further described herein.
  • a vitamin D compound includes vitamin D 2 compounds, vitamin D 3 compounds, isomers thereof, or derivatives/analogues thereof.
  • vitamin D compounds are vitamin D 3 compounds which are ligands of (more preferably are agonists of) the vitamin D receptor.
  • the vitamin D compound e.g., the vitamin D 3 compound
  • Vitamin D 1 compounds, vitamin D 2 compounds and vitamin D 3 compounds include, respectively, vitamin D 1 , D 2 , D 3 and analogues thereof.
  • the vitamin D compound may be a steroid, such as a secosteroid, e.g., calciol, calcidiol or calcitriol.
  • certain preferred vitamin D compounds in accordance with the invention include those described in U.S. Patent No. 6,492,353 and published international application WO2005/030222, which are incorporated herein by reference.
  • the term "obtaining” includes purchasing, synthesizing, isolating or otherwise acquiring one or more of the the vitamin D compounds used in practicing the invention.
  • the term "secosteroid" is art-recognized and includes compounds in which one of the cyclopentanoperhydro-phenanthrene rings of the steroid ring structure is broken.
  • 1-alpha,25(OH) 2 D 3 and analogues thereof are hormonally active secosteroids.
  • vitamin D 3 the 9-10 carbon-carbon bond of the B-ring is broken, generating a seco-B-steroid.
  • the official IUPAC name for vitamin D 3 is 9,10-secocholesta-5,7,10(19)-trien-3B-ol.
  • a 6-s-trans conformer of 1-alpha,25(OH) 2 D 3 is illustrated herein having all carbon atoms numbered using standard steroid notation.
  • a dotted line ( — ) indicating a substituent which is in the beta-orientation (i.e. , above the plane of the ring)
  • a wedged solid line ( ⁇ ⁇ ) indicating a substituent which is in the alpha-orientation (i.e. , below the plane of the molecule)
  • a wavy line ( ⁇ ) indicating that a substituent may be either above or below the plane of the ring.
  • ring A it should be understood that the stereochemical convention in the vitamin D field is opposite from the general chemical field, wherein a dotted line indicates a substituent on Ring A which is in an alpha-orientation (i.e. , below the plane of the molecule), and a wedged solid line indicates a substituent on ring A which is in the beta- orientation (i.e., above the plane of the ring). Furthermore the indication of stereochemistry across a carbon-carbon double bond is also opposite from the general chemical field in that "Z” refers to what is often referred to as a "cis” (same side) conformation whereas “E” refers to what is often referred to as a "trans” (opposite side) conformation. Regardless, both configurations, cis/trans and/or Z/E are contemplated for the compounds for use in the present invention.
  • the A ring of the hormone 1-alpha,25(OH) 2 D 3 contains two asymmetric centers at carbons 1 and 3, each one containing a hydroxyl group in well-characterized configurations, namely the 1 -alpha- and 3-beta- hydroxyl groups.
  • carbons 1 and 3 of the A ring are said to be "chiral carbons" or "carbon centers.”
  • the vitamin D compound is a compound of formula
  • X is hydroxyl or fluoro
  • Y is H 2 or CH 2 ;
  • Z 1 and Z 2 are H or a substituent represented by formula (IV), provided Z 1 and Z 2 are different (preferably Z 1 and Z 2 do not both represent formula (IV)):
  • Z 3 represents the above-described formula (III);
  • Ri, R 2 , and Z 4 are each, independently, hydrogen, alkyl, or a saturated or unsaturated carbon chain represented by formula (V), provided that at least one of Ri, R 2 , and Z 4 is the saturated or unsaturated carbon chain represented by formula (V) and provided that all of Ri, R 2 , and Z 4 are not saturated or unsaturated carbon chain represented by formula (V):
  • Z 5 represents the above-described formula (IV); A 2 is a single bond, a double bond, or a triple bond; and A 3 is a single bond or a double bond; and
  • R 3 , and R 4 are each, independently, hydrogen, alkyl, haloalkyl, hydroxyalkyl; and R 5 is H 2 or oxygen. R 5 may also represent hydrogen or may be absent.
  • the vitamin D compound is a compound of formula (Vl):
  • Xi and X 2 are H 2 or CH 2 , wherein X 1 and X 2 are not CH 2 at the same time;
  • A is a single or double bond
  • a 2 is a single, double or triple bond
  • a 3 is a single or double bond
  • Ri and R 2 are hydrogen, C r C 4 alkyl or 4-hydroxy-4-methylpentyl, wherein R 1 and R 2 are not both hydrogen;
  • R 5 is H 2 or oxygen, R 5 may also represent hydrogen or may be absent;
  • R 3 is CrC 4 alkyl, hydroxyalkyl or haloalkyl, eg., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl; and
  • R 4 is CrC 4 alkyl, hydroxyalkyl or haloalkyl, eg., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl.
  • the vitamin D compound is a compound of formula (VII):
  • Xi and X 2 are H 2 or CH 2 , wherein X 1 and X 2 are not CH 2 at the same time;
  • A is a single or double bond
  • a 2 is a single, double or triple bond
  • a 3 is a single or double bond
  • R 1 and R 2 are hydrogen, C 1 -C 4 alkyl, wherein R 1 and R 2 are not both hydrogen;
  • R 5 is H 2 or oxygen, R 5 may also represent hydrogen or may be absent;
  • R 3 is C 1 -C 4 alkyl, hydroxyalkyl or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl; and
  • R 4 is C 1 -C 4 alkyl, hydroxyalkyl haloalkyl, e.g., or fluoroalkyl, e.g., fluoromethyl and trifluoromethyl.
  • the vitamin D compound is a "geminal" compound of formula
  • a 2 is a single, a double or a triple bond
  • R 3 is CrC 4 alkyl, hydroxyalkyl, or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl;
  • R 4 is CrC 4 alkyl, hydroxyalkyl or haloalkyl, e.g., fluoroalkyl, e.g., fluoromethyl and trifluoromethyl; and the configuration at C 20 is R or S.
  • An example geminal compound of formula (VIII) is 1 ,25-dihydroxy-21-(3-hydroxy-3- methylbutyl)-19-nor-cholecalciferol:
  • the vitamin D compound is a compound of formula (IX):
  • A is a single or double bond
  • Ri and R 2 are each, independently, hydrogen, alkyl (for example methyl);
  • R 3 , and R 4 are each, independently, alkyl
  • X is hydroxyl or fluoro.
  • the vitamin D compound is a compound having formula (X):
  • Ri and R 2 are each, independently, hydrogen, or alkyl, e.g., methyl;
  • R 3 is alkyl, e.g., methyl
  • R 4 is alkyl, e.g., methyl
  • the vitamin D compound is selected from the group consisting of:
  • the vitamin D compound is selected from the group consisting of:
  • the vitamin D compound is selected from the group of geminal compounds consisting of:
  • the vitamin D compound is a geminal compound of formula (Xl):
  • a 1 is a single or double bond
  • a 2 is a single, a double or a triple bond
  • R 3 and R 4 are each independently CrC 4 alkyl, d-C 4 deuteroalkyl, hydroxyalkyl, or haloalkyl;
  • R 5 , R 6 and R 7 are each independently hydroxyl, OC(O)Ci -C 4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl; the configuration at C 20 is R or S;
  • R 5 , R 6 and R 7 are hydroxyl. In other embodiments, R 6 and R 7 are each acetyloxy.
  • Z is hydrogen when at least one of Ri and R 2 is CrC 4 deuteroalkyl and at least one of R 3 and R 4 is haloalkyl or when at least one of Ri and R 2 is haloalkyl and at least one of R 3 and R 4 is d-C 4 deuteroalkyl;
  • Z is - OH.
  • Still other embodiments of of formula (Xl) include those wherein X 1 is CH 2 ; A 2 is a single bond; R 1 , R 2 , R 3 , and R 4 are each independently methyl or ethyl; and Z is -OH.
  • X 1 is H 2 ; A 2 is a single bond; R 1 , R 2 , R 3 , and R 4 are each independently methyl or ethyl; the configuration at C 20 is S; and Z is -OH.
  • X 1 is H 2 ;
  • a 2 is a single bond;
  • R 1 , R 2 , R 3 , and R 4 are advantageously each methyl.
  • the haloalkyl is fluoroalkyl.
  • fluoroalkyl is fluoromethyl or trifluoromethyl.
  • Additional embodiments of of formula (Xl) include compounds X 1 is H 2 ; A 2 is a triple bond; R 1 and R 2 are each C 1 -C 4 deuteroalkyl; R 3 and R 4 are each haloalkyl; and Z is hydrogen.
  • X 1 is CH 2 ; A 2 is a triple bond; R 1 and R 2 are each C 1 -C 4 deuteroalkyl; R 3 and R 4 are each haloalkyl; and Z is hydrogen.
  • R 1 and R 2 are advantageously each deuteromethyl and R 3 and
  • R 4 are advantageously each trifluoromethyl.
  • the vitamin D compound is a geminal compound of formula (XII):
  • a 2 is a single, a double or a triple bond
  • Xi is CH 2 .
  • a 2 is a single bond.
  • R 1 , R 2 , R 3 , and R 4 are each independently methyl or ethyl.
  • Z is -OH.
  • X 1 is CH 2 ;
  • a 2 is a single bond;
  • R 1 , R 2 , R 3 , and R 4 are each independently methyl or ethyl; and
  • Z is -OH.
  • R 1 , R 2 , R 3 , and R 4 are each methyl.
  • the vitamin D compound is a geminal compound of the formula:
  • the vitamin D compound is a compound of formula (XIII):
  • Ri and R 2 are each independently, hydroxyl, OC(O)CrC 4 alkyl, OC(O)hydroxyalkyl, OC(O)fluororalkyl;
  • R 3 and R 4 are each independently hydrogen, d-C 4 alkyl, hydroxyalkyl or haloalkyl, or R 3 and R 4 taken together with C 20 form C 3 -C 6 cylcoalkyl; and
  • R 5 and R 6 are each independently CrC 4 alkyl and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • R 3 and R 4 are each independently hydrogen, C r
  • R 5 and R 6 are each independently C r C 4 alkyl.
  • R 5 and R 6 are each independently haloalkyl e.g., C r C 4 fluoroalkyl.
  • R 3 and R 4 are taken together with C20 to form C 3 -C 6 cycloalkyl, an example is cyclopropyl.
  • Xi and X 2 are each H 2 .
  • R 3 is hydrogen and R 4 is CrC 4 alkyl.
  • R 4 is methyl.
  • R 5 and R 6 are each independently methyl, ethyl fluoromethyl or trifluoromethyl. In a preferred embodiment, R 5 and R 6 are each methyl.
  • Ri and R 2 are each independently hydroxyl or OC(O)CrC 4 alkyl.
  • Ri and R 2 are each OC(O)CrC 4 alkyl. In another preferred embodiment, Ri and R 2 are each acetyloxy.
  • I .S-O-diacetyl-i ⁇ -dihydroxy-i ⁇ -ene ⁇ -keto-i ⁇ - nor-cholecalciferol having the following structure:
  • the vitamin D compound for use in accordance with the invention is 2-methylene-19-nor-20(S)-1 -alpha, 25-hydroxyvitamin D 3 :
  • the vitamin D compound is a compound of the formula (XIV):
  • a 1 is single or double bond
  • a 2 is a single, double or triple bond
  • R 3 , R 4 and R 5 are each independently hydrogen, C r C 4 alkyl, hydroxyalkyl, or haloalkyl, or R 3 and R 4 taken together with C 20 form C 3 -C 6 cycloalkyl;
  • R 6 and R 7 are each independently Ci -4 alkyl or haloalkyl; and R 8 is H, -COCrC 4 alkyl (e.g. Ac), -CO hydroxyalkyl or -COhaloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • R 8 is H, -COCrC 4 alkyl (e.g. Ac), -CO hydroxyalkyl or -COhaloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • R 6 and R 7 are each independently haloalkyl.
  • R 8 may suitably represent H or Ac.
  • a 1 is a single bond and A 2 is a single bond, E or Z double bond, or a triple bond.
  • a 1 is a double bond and A 2 is a single bond, E or Z double bond, or a triple bond.
  • R 5 is absent
  • X 1 and X 2 are each H.
  • X 1 is CH 2 and X 2 is H 2 .
  • R 3 is hydrogen and R 4 is C 1 -C 4 alkyl. In a preferred embodiment R 4 is methyl.
  • R 1 and R 2 both represent OAc.
  • R 6 and R 7 are each independently C 1- 4 alkyl. In another set of example compounds R 6 and R 7 are each independently haloalkyl. In another embodiment, R 6 and R 7 are each independently methyl, ethyl or fluoroalkyl. In a preferred embodiment, R 6 and R 8 are each trifluoroalkyl, e.g., trifluoromethyl.
  • R 5 represents hydrogen
  • vitamin D compounds for use in accordance with the invention are represented by formula (XV):
  • a 1 is single or double bond
  • a 2 is a single, double or triple bond;
  • Ri and R 2 are each independently OH, OC(O)CrC 4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl;
  • R 3 , R 4 and R 5 are each independently hydrogen, C r C 4 alkyl, hydroxyalkyl, or haloalkyl, or R 3 and R 4 taken together with C 20 form C 3 -C 6 cycloalkyl; R 6 and R 7 are each independently haloalkyl; and
  • R 8 is H, C(O)CrC 4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • An example compound of the above-described formula (XV) which is one of the preferred compounds in the context of the present invention is 1,3-di-O-acetyl-1 ,25-dihydroxy- I ⁇ SZ-diene ⁇ Z-hexafluoro-i ⁇ -nor-cholecalciferol:
  • the compound is one of formula (XVI), wherein R 1 and R 2 are each OAc; A 1 is a double bond; A 2 is a triple bond; and R 8 is either H or Ac:
  • vitamin D compounds for use in accordance with the invention are represented by the formula (XVII):
  • vitamin D compounds for use in accordance with the invention are represented by the formula (XVIII):
  • Xi CH 2 and X 2 is H 2 .
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • X 1 and X 2 are each H 2 .
  • a 1 is a single bond
  • a 2 is a triple bond, it is preferred that R 8 is H or C(O)CH 3 , and R 6 and R 7 are alkyl or haloalkyl. It is preferred that the alkyl group is methyl, and the haloalkyl group is trifluoroalkyl, preferably trifluoromethyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are haloalkyl, preferably trifluoroalkyl, preferably trifluoromethyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • a preferred compound of formula (XVIII) is 1,3-di-O-acetyl-1 ,25-dihydroxy-20- cyclopropyl-23E-ene-26,27-hexafluoro-19-nor-cholecalciferol:
  • Compound A I .S-Di-O-acetyl-i ⁇ -dihydroxy ⁇ O-cyclopropyl- cholecalciferol (referred to as "Compound A" in examples herein) having the formula:
  • esters and salts of Compound A include pharmaceutically acceptable labile esters that may be hydrolysed in the body to release Compound A.
  • Salts of Compound A include adducts and complexes that may be formed with alkali and alkaline earth metal ions and metal ion salts such as sodium, potassium and calcium ions and salts thereof such as calcium chloride, calcium malonate and the like.
  • Compound A may be administered as a pharmaceutically acceptable salt or ester thereof, preferably Compound A is employed as is i.e., it is not employed as an ester or a salt thereof.
  • Another compound is 1 ,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol having the formula:
  • esters and salts of 1 ,25-dihydroxy-20,21,28- cyclopropyl-cholecalciferol include pharmaceutically acceptable labile esters that may be hydrolysed in the body to release 1 ,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol.
  • Salts of 1,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol include adducts and complexes that may be formed with alkali and alkaline earth metal ions and metal ion salts such as sodium, potassium and calcium ions and salts thereof such as calcium chloride, calcium malonate and the like.
  • 1 ,25-dihydroxy-20,21 ,28-cyclopropyl-cholecalciferol may be administered as a pharmaceutically acceptable salt or ester thereof, preferably it is employed as is i.e., it is not employed as an ester or a salt thereof.
  • vitamin D compounds for use in the invention are compounds of the formula (XIX):
  • X is H 2 or CH 2 ;
  • Ri is hydrogen, hydroxy or fluorine
  • R 2 is hydrogen or methyl
  • R 3 is hydrogen or methyl, though when R 2 or R 3 is methyl, the other of R 3 or R 2 must be hydrogen;
  • R 4 is methyl, ethyl or trifluoromethyl
  • R 5 is methyl, ethyl or trifluoromethyl
  • A is a single or double bond
  • B is a single, E-double, Z-double or triple bond.
  • each of R 4 and R 5 is methyl or ethyl, for example 1-alpha- fluoro ⁇ S-hydroxy-i ⁇ E-diene ⁇ Z-bishomo ⁇ O-epi-cholecalciferol having the formula:
  • B is single, double, or triple bond
  • Xi and X 2 are each independently H 2 or CH 2 , provided Xi and X 2 are not both CH 2 ;
  • R 4 and R 5 are each independently alkyl or haloalkyl.
  • Examples of compounds of formula (XX) include the following:
  • vitamin D compound of the invention is 1 ,25-dihydroxy-21(3-hydroxy-3- trifluoromethyM-trifluoro-butynyl ⁇ Z-hexadeutero-i ⁇ -nor ⁇ OS-cholecalciferol.
  • a 1 is a double bond
  • Xi CH 2 and X 2 is H 2 .
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl or haloalkyl. It is preferred that the alkyl group is methyl and the haloalkyl group is trifluoroalkyl, preferably trifluoromethyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl. It is also preferred that R 6 and R 7 are independently alkyl and haloalkyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • a 1 is a double bond
  • X 1 and X 2 are each H 2 .
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl or haloalkyl. It is preferred that the alkyl group is methyl or ethyl and the haloalkyl group is trifluoroalkyl, preferably trifluoromethyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are haloalkyl, preferably trifluoroalkyl, preferably trifluoromethyl.
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • Ri and R 2 are OC(O)CH 3
  • a 1 is a single bond
  • a 2 is a single, double or triple bond, except that when R 3 is H and R 4 is methyl, A 2 is a double or triple bond.
  • R 3 is H
  • R 4 is methyl
  • R 5 is absent
  • R 8 is H or C(O)CH 3
  • R 6 and R 7 are alkyl, preferably methyl.
  • Preferred compounds of the present include the following: 1,3-Di-O-acetyl-1 ,25- dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor-cholecalciferol, 1 ,3-Di-O-acetyl-1 ,25- Dihydroxy-i ⁇ -ene ⁇ S-yne ⁇ e ⁇ Z-hexafluoro-i ⁇ -nor-cholecalciferol, 1,3,25-Tri-O-acetyl-1 ,25- Dihydroxy-16-ene-23-yne-26,27-hexafluoro-19-nor-cholecalciferol, 1,3-Di-O-acetyl-1 ,25- dihydroxy-i ⁇ -ene ⁇ S-yne-cholecalciferol, 1,3-Di-O-acetyl-1,25-dihydroxy-16,23E-diene- cholecalciferol, 1 ,3-Di-O-ace
  • vitamin D compounds for use in accordance with the invention include those having formula (XXII):
  • a 1 is single or double bond
  • a 2 is a single, double or triple bond
  • X 1 and X 2 are each independently H 2 or CH 2 , provided X 1 and X 2 are not both CH 2 ;
  • Ri and R 2 are each independently OH, OC(O)CrC 4 alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl;
  • R 3 , R 4 and R 5 are each independently hydrogen, d-C 4 alkyl, hydroxyalkyl, or haloalkyl, or R 3 and R 4 taken together with C 20 form C 3 -C 6 cylcoalkyl; R 6 and R 7 are each independently haloalkyl; and
  • R 8 is H, C(O)CrC 4 alkyl, C(O)hydroxyalkyl, or C(O)haloalkyl; and pharmaceutically acceptable esters, salts, and prodrugs thereof.
  • R 6 and R 7 are each independently trihaloalkyl, especially trifluoromethyl.
  • a vitamin D compound of particular interest is calcitriol.
  • vitamin D receptor agonists include paricalcitol (ZEMPLARTM) (see US Patent 5,587,497), tacalcitol (BONALFATM) (see US Patent 4,022,891), doxercalciferol (HECTOROLTM) (see Lam et al. (1974) Science 186, 1038), maxacalcitol (OXAROLTM) (see US Patent 4,891,364), calcipotriol (DAIVONEXTM) (see US Patent 4,866,048), and falecalcitriol (FULSTANTM).
  • ZEMPLARTM paricalcitol
  • BONALFATM tacalcitol
  • HECTOROLTM doxercalciferol
  • OFECTOROLTM maxacalcitol
  • OXAROLTM calcipotriol
  • DAIVONEXTM see US Patent 4,866,048)
  • falecalcitriol FULSTANTM
  • the structures of some of the compounds of the invention include asymmetric carbon atoms. Accordingly, it is to be understood that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention, unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and/or by stereochemically controlled synthesis.
  • Naturally occurring or synthetic isomers can be separated in several ways known in the art. Methods for separating a racemic mixture of two enantiomers include chromatography using a chiral stationary phase (see, e.g., "Chiral Liquid Chromatography,” W.J. Lough, Ed. Chapman and Hall, New York (1989)). Enantiomers can also be separated by classical resolution techniques. For example, formation of diastereomeric salts and fractional crystallization can be used to separate enantiomers.
  • the diastereomeric salts can be formed by addition of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and the like.
  • diastereomeric esters can be formed with enantiomerically pure chiral alcohols such as menthol, followed by separation of the diastereomeric esters and hydrolysis to yield the free, enantiomerically enriched carboxylic acid.
  • the compounds of the invention may be administered via ocular delivery, for example, through an ocular device suitable for direct implantation into the eye.
  • Such devices of the present invention are surprisingly found to provide sustained controlled release of various compositions to treat the eye without risk of detrimental local and systemic side effects.
  • An object of the present ocular method of delivery is to maximize the amount of drug contained in an intraocular device while minimizing its size in order to prolong the duration of the implant. See, e.g., U.S. Patents 5,378,475; 5,773,019; 6,001,386; 6,217,895, 6,375,972, and 6,756,058 and U.S. Publications 2005/0096290 and 2005/01269448.
  • Other methods of delivery include: an ocular delivery system that could be applied to an intra-ocular lens to prevent inflammation or posterior capsular opacification, an ocular delivery system that could be inserted directly into the vitreous, under the retina, or onto the sclera, and wherein inserting can be achieved by injecting the system or surgically implanting the system, a sustained release drug delivery system, and a method for providing controlled and sustained administration of an agent effective in obtaining a desired local or systemic physiological or pharmacological effect comprising surgically implanting a sustained release drug delivery system at a desired location.
  • a sustained release drug delivery system comprising an inner reservoir comprising an effective amount of an agent effective in obtaining a desired local or systemic physiological or pharmacological effect, an inner tube impermeable to the passage of said agent, said inner tube having first and second ends and covering at least a portion of said inner reservoir, said inner tube sized and formed of a material so that said inner tube is capable of supporting its own weight, an impermeable member positioned at said inner tube first end, said impermeable member preventing passage of said agent out of said reservoir through said inner tube first end, and a permeable member positioned at said inner tube second end, said permeable member allowing diffusion of said agent out of said reservoir through said inner tube second end; a method for administering a compound of the invention to a segment of an eye, the method comprising the step of implanting a sustained release device to deliver the compound of the invention to the vitreous of the eye or an implantable, sustained release device for administering a compound of the invention to a segment of
  • Still other methods of delivery include ointments or drops for topical application to the eye.
  • Such formulations are especially appropriate for the treatment of uveitis in the anterior portion of the eye.
  • the methods are particularly suitable for treating ocular conditions related to uveitis.
  • the devices are also particularly suitable for use as an ocular device in treating subjects suffering from ocular conditions wherein the device is surgically implanted within the vitreous of the eye.
  • the invention also provides a pharmaceutical composition, comprising an effective amount of a vitamin D compound as described herein and a pharmaceutically acceptable carrier.
  • the effective amount is effective to treat uveitis, as described previously.
  • the vitamin D compound is administered to the subject using a pharmaceutically-acceptable formulation, e.g., a pharmaceutically-acceptable formulation that provides sustained delivery of the vitamin D compound to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.
  • a pharmaceutically-acceptable formulation e.g., a pharmaceutically-acceptable formulation that provides sustained delivery of the vitamin D compound to a subject for at least 12 hours, 24 hours, 36 hours, 48 hours, one week, two weeks, three weeks, or four weeks after the pharmaceutically-acceptable formulation is administered to the subject.
  • these pharmaceutical compositions are suitable for topical or oral administration to a subject.
  • the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1 ) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, boluses, powders, granules, pastes; (2) parenteral administration, for example, by subcutaneous, intramuscular or intravenous injection as, for example, a sterile solution or suspension, (3) topical application, for example, as a cream, ointment or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; or (5) aerosol, for example, as an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • pharmaceutically acceptable refers to those vitamin D compounds of the present invention, compositions containing such compounds, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically-acceptable carrier includes pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ, or portion of the body, to another organ, or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically- acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide
  • wetting agents such as sodium laur ⁇ l sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • compositions containing a vitamin D compound(s) include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 1 per cent to about ninety-nine percent of active ingredient, preferably from about 5 per cent to about 70 per cent, most preferably from about 10 per cent to about 30 per cent.
  • compositions include the step of bringing into association a vitamin D compound(s) with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a vitamin D compound with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a vitamin D compound(s) as an active ingredient.
  • a compound may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example,
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the vitamin D compound(s) include pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solub
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active vitamin D compound(s) may contain suspending agents as, for example, ethoxylated isostear ⁇ l alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostear ⁇ l alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more vitamin D compound(s) with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • compositions of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a vitamin D compound(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active vitamin D compound(s) may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to vitamin D compound(s) of the present invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a vitamin D compound(s), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • the vitamin D compound(s) can be alternatively administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A nonaqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically-acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • Transdermal patches have the added advantage of providing controlled delivery of a vitamin D compound(s) to the body.
  • dosage forms can be made by dissolving or dispersing the agent in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the active ingredient across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the active ingredient in a polymer matrix or gel.
  • compositions of the invention suitable for parenteral administration comprise one or more vitamin D compound(s) in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • antibacterial and antifungal agents for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • isotonic agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the absorption of the drug in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of vitamin D compound(s) in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • kits for treatment or prevention of a disease or disorder or symptoms thereof associated withuveitis includes an effective amount of a compound in unit dosage form, together with instructions for administering the compound to a subject suffering from or susceptible to uveitis, wherein the effective amount of compound is less than 500 mg of the compound.
  • the kit comprises a sterile container which contains the compound; such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister- packs, or other suitable container form known in the art.
  • sterile container which contains the compound; such containers can be boxes, ampules, bottles, vials, tubes, bags, pouches, blister- packs, or other suitable container form known in the art.
  • Such containers can be made of plastic, glass, laminated paper, metal foil, or other materials suitable for holding medicaments.
  • the instructions will generally include information about the use of the compound for treatment of a disease or disorder or symptoms thereof associated with uveitis; in preferred embodiments, the instructions include at least one of the following: description of the compound; dosage schedule and administration for treatment of uveitis or symptoms thereof; precautions; warnings; indications; counter-indications; overdosage information; adverse reactions; animal pharmacology; clinical studies; and/or references.
  • the instructions may be printed directly on the container (when present), or as a label applied to the container, or as a separate sheet, pamphlet, card, or folder supplied in or with the container.
  • vitamin D compound(s) When administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically-acceptable carrier.
  • the vitamin D compound(s), which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels and time course of administration of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • An exemplary dose range is from 0.1 to 300 ug per day
  • a preferred dose of the vitamin D compound for the present invention is the maximum that a patient can tolerate and not develop hypercalcemia.
  • the vitamin D compound of the present invention is administered at a concentration of about 0.001 ug to about 100 ug per kilogram of body weight, about 0.001 to about 10 ug/kg or about 0.001 ug to about 100 ug/kg of body weight. Ranges intermediate to the above-recited values are also intended to be part of the invention.
  • the vitamin D compound may be administered separately, sequentially or simultaneously in separate or combined pharmaceutical formulations with a second medicament for the treatment of uveitis (for example a second vitamin D compound of the present invention).
  • 0.0797 g of 1 ,25-dihydroxy-20-cyclopropyl-cholecalciferol was dissolved in 0.8 mL of pyridine, cooled to ice-bath temperature and 0.2 mL of acetic anhydride was added. The solution was refrigerated overnight. The solution was then diluted with 1 ml. of water, stirred for 10 min in the ice bath and distributed between 10 ml. of water and 25 ml. of ethyl acetate. The organic layer was washed with 3x10 ml. of water, once with 5 ml. of saturated sodium hydrogen carbonate, once with 3 ml.
  • vitamin D compound eg VDR agonists such as Vitamin D3 analogues can have an effect on uveitis has been proven in an in vivo model.
  • EAU an autoimmune disease mediated by TM -type uveitogenic CD4+ T-cells, serves as a model for human posterior uveitis.
  • E ⁇ AU-susceptible B10.RIII mice were immunized with an uveitogenic regimen of 8 ug of interphotoreceptor retinoid-binding protein (IRBP) in CFA and treated orally with calcitriol or with Compound A, before or after EAU induction.
  • IRBP interphotoreceptor retinoid-binding protein
  • Figure 2 shows the EAU disease score (quantitated between 0 and 4) at day 21.
  • calcitriol at 0.5 ug/kg and Compound A at 10 ⁇ g/kg can prevent EAU, when administered from day -6 to 2.
  • Compound A but not calcitriol could inhibit EAU development when treatment was started 7 days after immunization.
  • protected mice had reduced antigen-specific delayed type hypersensitivity (DTH) responses to IRBP. It can be concluded that delayed hypersensitivity to IRBP in treated mice is correlated with disease severity.
  • LN primed lymph node cells
  • IFN-gamma is a signature cytokine for Th1 cells
  • IL-7 is a signature cytokine of pathogenic T cells. Both of these cytokines have been found to be produced by pathogenic T-cells in TM- type autoimmune diseases. That there is apparently no effect on IL-4 which is a Th2 cell signature cytokine implies a selectivity in the treatment for effect on a TM response over a Th2 response.
  • Vitamin D 3 derivatives as shown in Figure 5.
  • Vitamin D compounds eg VDR agonists
  • the inventors have demonstrated that natural Vitamin D 3 (calcitriol) effectively prevents E ⁇ AU whilst a synthetic vitamin D compound (a VDR agonist) Compound A, is capable of preventing as well as treating EAU.
  • Compound B a Vitamin D compound (1 ⁇ -Fluoro-25-hydroxy-16-ene- 23-yne-20-cyclopropyl-cholecalciferol) was found to be ineffective in inhibiting EAU in this model.
  • IRPB interphotoreceptor retinoid binding protein
  • CFA Complete Freund's adjuvant
  • TARC T-cell activation regulatory chemokine
  • EAU experimental autoimmune uveoretinitis LN - lymph nodes Incorporation by Reference

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Abstract

L'invention concerne l'utilisation de composés à base de vitamine D pour la prophylaxie ou le traitement de l'uvéite.
PCT/EP2006/061415 2005-09-19 2006-04-06 Utilisation de composes a base de vitamine d3 pour traiter l'uveite WO2007039322A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013026557A1 (fr) * 2011-08-19 2013-02-28 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Agent de polythérapie contenant des vasoconstricteurs
WO2019164222A1 (fr) * 2018-02-20 2019-08-29 Chong Kun Dang Pharmaceutical Corp. Composition permettant de prévenir ou de traiter l'uvéite
US11571426B2 (en) 2017-11-24 2023-02-07 Chong Kun Dang Pharmaceutical Corp. Compositions for preventing or treating lupus

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0815862A1 (fr) * 1995-03-20 1998-01-07 Katsuhiko Mukai Composition ophthamologique comprenant de la vitamine d activee
EP1059085A1 (fr) * 1998-02-26 2000-12-13 Chugai Seiyaku Kabushiki Kaisha Inhibiteurs de migration de cellules de langerhans
US20040167105A1 (en) * 1997-09-08 2004-08-26 Manchand Percy Sarwood 1,3-dihydroxy-20,20-dialkyl-vitamin D3 analogs
WO2005030222A1 (fr) * 2003-09-24 2005-04-07 Bioxell S.P.A. Composes de la vitamine d3 1,3-diaclyatee,26,27-alkyle/haloalkyle et procedes d'utilisation associes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0815862A1 (fr) * 1995-03-20 1998-01-07 Katsuhiko Mukai Composition ophthamologique comprenant de la vitamine d activee
US20040167105A1 (en) * 1997-09-08 2004-08-26 Manchand Percy Sarwood 1,3-dihydroxy-20,20-dialkyl-vitamin D3 analogs
EP1059085A1 (fr) * 1998-02-26 2000-12-13 Chugai Seiyaku Kabushiki Kaisha Inhibiteurs de migration de cellules de langerhans
WO2005030222A1 (fr) * 2003-09-24 2005-04-07 Bioxell S.P.A. Composes de la vitamine d3 1,3-diaclyatee,26,27-alkyle/haloalkyle et procedes d'utilisation associes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BECKER M D ET AL: "Management of sight-threatening uveitis: New therapeutic options", DRUGS 2005 NEW ZEALAND, vol. 65, no. 4, 2005, pages 497 - 519, XP009070079, ISSN: 0012-6667 *
CRESCIOLI C ET AL: "Inhibition of prostate cell growth by BXL-628, a calcitriol analogue selected for a phase II clinical trial in patients with benign prostate hyperplasia", EUROPEAN JOURNAL OF ENDOCRINOLOGY, vol. 150, no. 4, April 2004 (2004-04-01), pages 591 - 603, XP002392301, ISSN: 0804-4643 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013026557A1 (fr) * 2011-08-19 2013-02-28 Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh Agent de polythérapie contenant des vasoconstricteurs
US11571426B2 (en) 2017-11-24 2023-02-07 Chong Kun Dang Pharmaceutical Corp. Compositions for preventing or treating lupus
WO2019164222A1 (fr) * 2018-02-20 2019-08-29 Chong Kun Dang Pharmaceutical Corp. Composition permettant de prévenir ou de traiter l'uvéite
RU2757273C1 (ru) * 2018-02-20 2021-10-12 Чонг Кун Данг Фармасьютикал Корп. Композиции для предупреждения или лечения увеита

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